Methods and compositions for treating or preventing erythema

ABSTRACT

Methods and products for treating or preventing erythema or a symptom associated with erythema in a subject are described. The methods involve topically applying to an affected skin area a topical aqueous gel composition comprising about 0.01% to about 10% by weight of at least one α-adrenergic receptor agonist and a pharmaceutically acceptable carrier.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.14/084,172, filed Nov. 19, 2013, which is a continuation of U.S. patentapplication Ser. No. 13/791,059, filed Mar. 8, 2013, issued as U.S. Pat.No. 8,586,586 on Nov. 19, 2013, which is a continuation of U.S. patentapplication Ser. No. 13/072,104, filed Mar. 25, 2011, issued as U.S.Pat. No. 8,410,102 on Apr. 2, 2013, which is a continuation-in-part ofU.S. patent application Ser. No. 12/544,663, filed Aug. 20, 2009, issuedas U.S. Pat. No. 8,231,885 on Jul. 31, 2012, which is acontinuation-in-part of U.S. patent application Ser. No. 11/449,079filed Jun. 8, 2006, issued as U.S. Pat. No. 7,838,563 on Nov. 23, 2010,which is a continuation-in-part of U.S. patent application Ser. No.10/853,585 filed May 25, 2004, issued as U.S. Pat. No. 7,439,241 on Oct.21, 2008, which claims priority to U.S. Provisional Patent ApplicationNo. 60/473,611, filed May 27, 2003. U.S. patent application Ser. No.13/072,104 is also entitled to priority pursuant to 35 U.S.C. §119(e) toU.S. Provisional Patent Application No. 61/282,754, filed Mar. 26, 2010.The contents of all of these applications are hereby incorporated byreference in their entireties.

BACKGROUND OF THE INVENTION

Erythema is a skin condition characterized by redness or rash of theskin. It occurs with any skin injury, infection, or inflammation. It canalso occur as a reaction to medications, illness or emotions. It canfurther occur for reasons currently unknown. Erythema is difficult totreat. Currently available treatments for erythema mainly treat theunderlying diseases and avoid known triggers. These treatments are oflimited effectiveness, particularly for erythema with unknown causes.

It has been described that α adrenoceptor agonists, such as brimonidineand oxymetazoline, can be used for topical treatment of erythema. SeeU.S. Pat. No. 7,439,241 to DeJovin et al., the priority of which isproperly claimed by the present application and the disclosure of whichis hereby incorporated by reference in its entirety; and U.S. Pat. No.7,812,049 to Shanler et al.

Side effects following topical administration of an α adrenoceptoragonist, particularly those resulting from systemic exposure, may imposelimitations on the chronic topical application of α adrenoceptoragonists to the skin. For example, brimonidine, available as either amonotherapy or an adjunctive therapy to lower intraocular pressure (IOP)in the treatment of glaucoma and ocular hypertension (OHT), can beabsorbed systemically to a limited extent following ophthalmicapplication as demonstrated by reduction in blood pressure and decreasein heart rate. The most common side effects associated with brimonidinetherapy are dry mouth, fatigue/drowsiness, headache, mild hyperemia,blurred vision and foreign body sensation. Hypertension, palpitationsand syncope have been reported by less than 3% patients in clinicaltrials involving brimonidine ophthalmic treatment. See McGhie, Journalof the Pharmacy Society of Wisconsin, May/June 2001, at World Wide Web:pswi.org/professional/pharmaco/brimonidine.pdf, and references therein.Results from the dose-ranging study in patients with glaucoma or ocularhypertension showed that although 0.5% (w/w) had higher efficacy in theearly phase of treatment, the 0.5% (w/w) and 0.2% (w/w) had similarefficacy after two weeks of treatment, and that 0.5% (w/w) had moresystemic and ocular side effects than 0.2% (w/w). See, e.g., Walters,Survey of Ophthalmology, 1996, 41: S19-S26). Ophthalmic formulationscontaining 0.2% (w/w) brimonidine have been used for chronicapplications to treat glaucoma and ocular hypertension, while thatcontaining 0.5% (w/w) brimonidine has been only used for acute therapyfor the prevention of postoperative intraocular pressure spikes. Inorder to reduce a variety of ocular and systemic side-effects associatedwith the ophthalmic application of 0.2% (w/w) brimonidine, ophthalmicformulations containing lower concentrations of brimonidine, e.g., 0.15%(w/w) or 0.1% (w/w), have been subsequently developed and used forchronic ophthalmic applications.

DeJovin et al. recognizes the need of a topical skin composition thatinsures that the α adrenoceptor agonists are effective in the skin of apatient but do not penetrate the skin in sufficient amounts to induceserious systemic side effects. It describes topical formulationscontaining an α adrenoceptor agonist at about 0.01% (w/w) to about 5%(w/w), preferably about 0.05% (w/w) to about 1% (w/w), more preferablyabout 0.1% (w/w) to about 0.2% (w/w), for treating erythema associatedwith rosacea. It provides examples on various possible topicalformulations that can be used for topical administration of αadrenoceptor agonists, e.g., aqueous solution topical formulation, creamtopical formulation, ointment formulation, and aqueous gel formulations.DeJovin et al. also includes examples demonstrating the therapeuticeffectiveness of α adrenoceptor agonists, such as brimonidine,oxymetazoline and naphazoline, in treating erythema. However, itcontains no example or illustration on the safety of the treatment.

To ensure the safety and avoid unacceptable side effects, a previousclinical study used 0.2% (w/w) brimonidine tartrate as the “high” dosagefor treating erythema. See US 2009/0061020 to Theobald et al.

Oxymetazoline, available in 0.025% (w/w) or 0.05% (w/w) solution as atopical decongestant, has been recommended not to be used for more thanthree days, because rebound congestion, rhinitis medicamentosa, andother side effects may occur, see Ramey et al., J Investig Allergol ClinImmunol 2006; Vol. 16(3): 148-155.

Shanler et al. describes the use of a composition comprising about 0.05%(w/w) to about 30% (w/w), preferably about 0.001% (w/w) up to about 3%(w/w), al adrenoceptor agonist, such as oxymetazoline, for treatingerythema resulting from rosacea. It generally describes that the“compositions according to the invention may comprise all pharmaceuticalforms normally utilized for the topical route of administration andknown to practitioners of this art including solutions, gels, lotionscreams, ointments, foams, mousses, emulsions, microemulsions, milks,serums, aerosols, sprays, dispersions, microcapsules, vesicles andmicroparticles thereof” Shanler et al. does not provide examples onpossible formulations that may be used, nor examples on theeffectiveness or safety of any treatment.

There remains the need of a safe and effective treatment of erythema ora related symptom by using a topical skin composition that delivers atherapeutically effective amount of a adrenoceptor agonist to theaffected skin area without causing unacceptable side effects.

In the present invention, it has been discovered that topicaladministration to an affected skin area an α adrenoceptor agonist, suchas brimonidine, in a topical aqueous gel composition resulted insignificantly less systemic exposure than topical ophthalmicapplication. It has been found that although systemic exposure increasedwith the applied dose of brimonidine, statistical analysis showed thatthe increase in systemic exposure (C_(max)) was not dose proportional,i.e., the increase in the mean C_(max) was much less than the increasein the dose. It has also been discovered that, unlike the topicalophthalmic application, topical administration to an affected skin areaa higher concentration of an α adrenoceptor agonist, such as 0.5% (w/w)brimonidine, in a topical aqueous gel composition resulted in increasedefficacy without observable loss of effectiveness over time. Nounacceptable adverse event was observed with the treatment of higherconcentration of an α-adrenergic receptor agonist tested.

Accordingly, it has unexpectedly been discovered that a topical aqueousgel composition has achieved superior clinical properties, e.g.,allowing more effective treatment of erythema without causingunacceptable side effect, even at higher concentrations of the αadrenoceptor agonist.

BRIEF SUMMARY OF THE INVENTION

In one general aspect, embodiments of the present invention relate to amethod of treating or preventing erythema or a symptom associatedtherewith in a subject, the method comprising topically administering toa skin area of the subject a topical composition comprising about 0.01%(w/w) to 10% (w/w) of at least one α 2-adrenergic receptor agonist and apharmaceutically acceptable carrier, wherein the skin area is, or isprone to be, affected by the erythema or the symptom associatedtherewith.

In another general aspect, embodiments of the present invention relateto a method of producing a packaged product for providing a safe andeffective treatment of erythema or a symptom associated therewith in asubject. The method comprises:

(1) obtaining a topical aqueous gel composition comprising about 0.01%(w/w) to about 10% (w/w) of at least one α adrenergic receptor agonistand a pharmaceutically acceptable carrier;

(2) devising instructions for topically administering the topicalaqueous gel composition to a skin area that is, or is prone to be,affected by the erythema or the symptom associated therewith to obtainthe safe and effective treatment, and

(3) providing the topical aqueous gel composition and the instructionsin a unified package.

In another general aspect, embodiments of the present invention relateto a method of treating or preventing erythema or a symptom associatedtherewith in a subject, the method comprising topically administering toa skin area of the subject a topical aqueous gel composition comprisingabout 0.01% (w/w) to 10% (w/w) of brimonidine or a pharmaceuticallyacceptable salt, and a pharmaceutically acceptable carrier, wherein theskin area is, or is prone to be, affected by the erythema or the symptomassociated therewith.

In yet another general aspect, embodiments of the present inventionrelate to a topical composition for providing a safe and effectivetreatment of erythema or a symptom associated therewith in a subject,comprising about 0.4 (w/w) to about 0.6% (w/w) brimonidine tartrate andabout 0.8% to 1.5% carbomer.

In a preferred embodiment, the α adrenergic receptor agonist used in orencompassed by embodiments of the present invention is selected from thegroup consisting of brimonidine, oxymetazoline and naphazoline.

In another preferred embodiment, the topical aqueous gel compositionused in or encompassed by embodiments of the present invention comprisesabout 0.4% (w/w) to about 0.6% (w/w) brimonidine tartrate.

In yet another preferred embodiment, the erythema is erythema ofrosacea.

Other aspects, features and advantages of the invention will be apparentfrom the following disclosure, including the detailed description of theinvention and its preferred embodiments and the appended claims.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The foregoing summary, as well as the following detailed description ofthe invention, will be better understood when read in conjunction withthe appended drawings. For the purpose of illustrating the invention,there are shown in the drawings embodiments which are presentlypreferred. It should be understood, however, that the invention is notlimited by the drawings.

In the drawings:

FIG. 1 illustrates composite success on Day 1, Day 15 and Day 29 afterthe initial treatment, using last observation carried forward (LOCF)approach in the intent to treat (ITT) population;

FIG. 2 illustrates CEA success on Day 1, Day 15 and Day 29 after theinitial treatment, using LOCF approach in the ITT population; and

FIG. 3 illustrates PSA-5 success on Day 1, Day 15 and Day 29 after theinitial treatment using LOCF approach in the ITT population.

DETAILED DESCRIPTION OF THE INVENTION

Various publications, articles and patents are cited or described in thebackground and throughout the specification, each of these references isherein incorporated by reference in its entirety. Discussion ofdocuments, acts, materials, devices, articles or the like which havebeen included in the present specification is for the purpose ofproviding context for the present invention. Such discussion is not anadmission that any or all of these matters form part of the prior artwith respect to any inventions disclosed or claimed.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood to one of ordinary skill inthe art to which this invention pertains. Otherwise, certain terms usedherein have the meanings as set in the specification. All patents,published patent applications and publications cited herein areincorporated by reference as if set forth fully herein. It must be notedthat as used herein and in the appended claims, the singular forms “a,”“an,” and “the” include plural reference unless the context clearlydictates otherwise.

As used herein, “erythema or a symptom associated therewith” is intendedto encompass any type or classification of abnormal skin rednessassociated with or resulting from rosacea, e.g., erythema or a symptomassociated therewith in a patient with rosacea. A major symptom ofrosacea is erythema, which is a skin disorder that generally affects thecheeks, nose, chin, and forehead of a patient.

The term “erythema or a symptom associated therewith” encompassesdifferent degrees or grades of erythema or a symptom associatedtherewith, from mild to severe.

For example, erythema or a symptom associated therewith can be rated bya clinician based on Clinician's Erythema Assessment Score (CEA) on ascale from 0 to 4, with 0 being clear skin with no signs of erythema; 1being almost clear, slight redness; 2 being mild erythema, definiteredness; 3 being moderate redness; and 4 being severe redness.

Erythema or a symptom associated therewith can also be rated by apatient based on Patient's Self Assessment (PSA, also called PSA-5herein) on a scale from 0 to 4, with 0 being no redness; 1 being verymild redness; 2 being mild redness; 3 being moderate redness and 4 beingsevere redness.

In view of the present disclosure, a skin area that is affected byerythema or that is prone to be affected by erythema can be identifiedusing any diagnostic signs or means known in the art, and can be treatedby methods according to embodiments of the present invention.

The efficacy of the treatment can be measured using method known in theart. For example, the efficacy can be measured by the grades ofimprovement as evaluated by CEA, PSA or the combination of CEA and PSA,and the duration of the improvement.

α-adrenergic receptor agonists of the present teachings include anyα-adrenergic receptor agonist known to skilled artisans. In someaspects, an α-adrenergic receptor agonist can be an α-adrenergicreceptor agonist selective for al-adrenergic receptors, an α-adrenergicreceptor agonist selective for α2-adrenergic receptors, or anα-adrenergic receptor agonist non-selective for either al orα2-adrenergic receptors.

As used herein, a selective α1-adrenergic receptor agonist is an agonistfor which the EC₅₀ with respect to an al-adrenergic receptor is lessthan the EC₅₀ with respect to an α2-adrenergic receptor, while aselective α2-adrenergic receptor agonist is an agonist for which theEC₅₀ with respect to an α2-adrenergic receptor is less than the EC₅₀with respect to an al-adrenergic receptor, wherein the EC₅₀ for anagonist is defined as the molar concentration of the agonist whichproduces 50% of the maximum possible response of a receptor to thatagonist.

Some non-limiting examples of α-adrenergic receptor agonists which canbe used in the present compositions and methods include: amphetamine,apraclonidine, brimonidine, clonidine, clonidine, dexmedetomidine,dextroamphetamine, dopamine, I-dobutamine, ephedrine, epinephrine,epinine (N-methyl-dopamine), ethylnorepinephrine, guanabenz, guanfacine,levarterenol, lofexidine, mephentermine, metaraminol, methamphetamine,methoxamine, α-methyldopa, α-methylnorepinephrine, methylphenidate,mivazerol, mitodrine, moxonidine, naphazoline, norepinephrine,norphenylephrine, oxymetazoline, pemolinepropylhexedrine, phenylephrine,phenylpropanolamine, propylhexedrine, tetrahydrozoline, tizanidine,xylometazoline,(8-bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,(8-bromo-quinoxalin-5-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,(5-bromo-3-methyl-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,(5-bromo-2-methoxy-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,(4,5-dihydro-1H-imidazol-2-yl)-(8-methyl-quinoxalin-6-yl)-amine, and(4,5-dihydro-1H-imidazol-2-yl)-quinoxalin-5-yl-amine.

Compositions of the present teachings include one or more α-adrenergicreceptor agonists, prodrugs thereof, pharmaceutically acceptable saltsthereof, hydrates thereof, solvates thereof and combinations thereof,such as those described in U.S. Pat. No. 7,439,241, which areincorporated herein by reference.

As used herein, the term “brimonidine” refers to the compound(5-bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine havingthe structure of formula (I):

and any pharmaceutically acceptable salt of the compound, including, butnot limited to, brimonidine tartrate.

The phrase “pharmaceutically acceptable salt(s)”, as used herein, meansthose salts of a compound of interest that are safe and effective fortopical use in mammals and that possess the desired biological activity.Pharmaceutically acceptable salts include salts of acidic or basicgroups present in the specified compounds. Pharmaceutically acceptableacid addition salts include, but are not limited to, hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, isonicotinate, acetate, lactate, salicylate, citrate,tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate,p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compoundsused in the present invention can form pharmaceutically acceptable saltswith various amino acids. Suitable base salts include, but are notlimited to, aluminum, calcium, lithium, magnesium, potassium, sodium,zinc, and diethanolamine salts. For a review on pharmaceuticallyacceptable salts see BERGE ET AL., 66 J. PHARM. SCI. 1-19 (1977),incorporated herein by reference.

The term “topical aqueous gel composition,” as used herein, means anyaqueous gel formulation or composition which is pharmaceutically and/orcosmetically acceptable for topical delivery of the specified compoundsaccording to embodiments of the invention.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredient in the specified amount, aswell as any product which results, directly or indirectly, fromcombinations of the specified ingredient in the specified amount.

As used herein, the term “subject” means any animal, preferably amammal, most preferably a human, to whom will be or has beenadministered compounds or topical formulations according to embodimentsof the invention. Preferably, a subject is in need of, or has been theobject of observation or experiment of, treatment or prevention oferythema or a symptom associated therewith.

As used herein, the term “instructions” when used in the context of apackaged product includes a publication, a recording, a diagram or anyother medium of expression which can be used to communicate theusefulness of the packaged product for its designated use. Theinstructions can, for example, be affixed to or included within acontainer for the packaged product.

As used herein, the term “treatment” or “treating” refers to anamelioration, prophylaxis, or reversal of erythema or a symptomassociated therewith, for example, by lessening or delaying the onset ofthe redness of the skin affected by the erythema or the symptom.

As used herein, a “safe and effective amount” means the amount of anα-adrenergic receptor agonist that is effective to treat erythema or asymptom associated therewith, without causing unacceptable drug relatedadverse events, when administered to a subject.

As used herein, the phrase “unacceptable drug related adverse events,”“unacceptable adverse drug events,” and “unacceptable adverse drugreaction,” shall all mean harm or undesired outcome associated with orcaused by a proposed use of a drug, and the harm or undesired outcomereaches such a severity that a regulatory agency deems the drugunacceptable for the proposed use.

It has been discovered in the present invention that topicaladministration of a topical aqueous gel composition comprising about0.01% to about 10% by weight of an α-adrenergic receptor agonist, suchas brimonidine, to a skin area affected by erythema or a symptomassociated therewith, provides effective treatment of erythema or asymptom associated therewith, without causing unacceptable drug relatedadverse events. For example, it has been discovered that topicaladministration to a skin area affected by erythema or a symptomassociated therewith with a topical aqueous gel composition comprisingincreasing concentration of an α-adrenergic receptor agonist, such asbrimonidine, resulted in a clear dosage responsive increase in theefficacy and an increase in the systemic exposure. However, statisticalanalysis showed that the increase in systemic exposure (C_(max)) was notdose proportional, e.g., the increase in mean C_(max) was much less thanthe increase in dose. It has also been discovered that, unlike thetopical ophthalmic application, topical administration to an affectedskin area a higher concentration of an α adrenoceptor agonist, such as0.5% (w/w) brimonidine, in a topical aqueous gel composition resulted inincreased efficacy without observable loss of efficacy over time. Nounacceptable adverse event was observed with the treatment of higherconcentrations of an α-adrenergic receptor agonist tested. Topical skintreatments of erythema or a symptom associated therewith with allconcentrations and regimens tested resulted in significantly lowersystemic exposure to brimonidine than the treatment with eye dropsapplied as recommended in the label of the ophthalmic products.

Such superior clinical activities of the topical aqueous gel compositioncomprising about 0.01% to about 10% by weight of an α-adrenergicreceptor agonist have not been previously reported. The presentdiscovery is surprising and unexpected, particularly in view of thepreviously reported efficacy and safety profiles of α-adrenergicreceptor agonists in other applications, such as brimonidine inophthalmic applications, where a significant loss of effectiveness overtime was seen with the brimonidine 0.5% (w/w) formulation and thechronic use of much lower concentrations of brimonidine, e.g., 0.1% or0.15% by weight, is preferred, because the lower concentrations provideimproved tolerability while maintaining IOP-lowering efficacy.

Accordingly, in one general aspect, embodiments of the present inventionrelate to a method of treating or preventing erythema or a symptomassociated therewith in a subject. The method comprising topicallyadministering to a skin area of the subject a topical aqueous gelcomposition comprising about 0.01% (w/w) to about 10% (w/w) of at leastone α adrenergic receptor agonist and a pharmaceutically acceptablecarrier, wherein the skin area is, or is prone to be, affected by theerythema or the symptom associated therewith.

According to an embodiment of the present invention, the topicaladministration of the topical aqueous gel composition comprising a safeand effective amount of brimonidine, such as about 0.01% (w/w) to about10% (w/w) brimonidine, to an affected skin area effects a serum orplasma profile of brimonidine having a mean C_(max) of about 54±28 pg/mLor less and a mean AUC_(0-24hr) of about 568±277 pg·hr/mL or less. Themean C_(max) and the mean AUC_(0-24hr) correspond to the serum or plasmaprofile of brimonidine after ophthalmic treatment with 0.2% (w/w)brimonidine tartrate eye drops as recommended in the label of theophthalmic product.

According to an embodiment of the present invention, upon topicallyadministering the topical aqueous gel formulation to the affected skinarea, the onset of noticeable effect, i.e., at least 1-grade improvementof the erythema or the symptom, is observed. When sufficiently highconcentration of an α adrenergic receptor agonist is included in thetopical aqueous gel formulation, the noticeable effect is thenprogressed to maximum improvement, which includes 2-grade improvement ofthe erythema or the symptom that lasts for a sustained period of time.The maximum improvement then declines to noticeable effect, which thendisappears. The grades of improvement of the erythema or the symptom canbe evaluated by Clinician's Erythema Assessment Score (CEA), a Patient'sSelf Assessment (PSA), or a combination of CEA and PSA.

According to an embodiment of the present invention, the topicaladministration of a topical aqueous gel composition comprising about0.01% (w/w) to about 10% (w/w) α adrenergic receptor agonist, such asbrimonidine, to a skin area affected by erythema or a symptom associatedtherewith results in significantly more effective treatment of theerythema and the symptom than a vehicle control for reduction of theerythema and the symptom as measured by a 12 hour success profileevaluated on both CEA and PSA scales, without causing any unacceptableadverse effect.

In one embodiment, the 12 hour success profile comprises at least1-grade improvement of the erythema or the symptom.

According to another embodiment of the present invention, the topicaladministration of a topical aqueous gel composition comprising about0.3% (w/w) to about 10% (w/w) α adrenergic receptor agonist, such asbrimonidine, to a skin area affected by erythema or a symptom associatedtherewith resulted in significantly more reduction of the erythema andthe symptom compared to a vehicle control as measured by a 12 hoursuccess profile evaluated on both CEA and PSA scales, without causingany unacceptable adverse effect. In a particular embodiment, theerythema and the symptom is facial erythema associated with rosacea.

In an embodiment of the present invention, the 12 hour success profilecomprises a noticeable effect of 1-grade improvement of the erythema orthe symptom and about 1 hour to about 8 hours of a 2-grade improvementof the erythema or the symptom. According to embodiments of the presentinvention, the 2-grade improvement lasts, for example, at least about 6hours, at least about 5 hours, at least about 4 hours, at least about 3hours, at least about 2 hours or at least about 1 hour, depending on theα adrenergic receptor agonist used, the applied dose, the particularsubject, the severity and complications of erythema being treated, etc.

In a preferred embodiment, the 12 hour success profile comprises anoticeable effect of 1-grade improvement of the erythema or the symptomand about 2 hours to about 7 hours of a 2-grade improvement of theerythema or the symptom.

In another preferred embodiment, the 12 hour success profile comprises anoticeable effect of 1-grade improvement of the erythema or the symptomand about 3 hours to about 6 hours of a 2-grade improvement of theerythema or the symptom.

In yet another preferred embodiment, the 12 hour success profilecomprises a noticeable effect of 1-grade improvement of the erythema orthe symptom and about 2 hours to about 5 hours of a 2-grade improvementof the erythema or the symptom.

In a preferred embodiment, the erythema is erythema of rosacea.

In an embodiment of the present invention, the topical aqueous gelcomposition comprises about 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.5%, 1.0%,1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%,7.5%, 8.0%, 8.5%, 9.0%, 9.5% or 10.0%, by weight of an α adrenergicreceptor agonist selected from the group consisting of brimonidine,oxymetazoline, naphazoline, tetrahydrozoline, xylometazoline,phenylephrine, methoxamine, mephentermine, metaraminol, midodrine,epinephrine and norepinephrine.

In another embodiment of the present invention, the topical aqueous gelcomposition comprises about 0.4%, about 0.45%, about 0.5%, about 0.55%or about 0.6%, by weight of an α adrenergic receptor agonist selectedfrom the group consisting of brimonidine, oxymetazoline, naphazoline,tetrahydrozoline, xylometazoline, phenylephrine, methoxamine,mephentermine, metaraminol, midodrine, epinephrine and norepinephrine.

In a preferred embodiment, the topical aqueous gel composition comprisesabout 0.5% by weight of an α adrenergic receptor agonist, such as about0.5% by weight of brimonidine tartrate, or 0.5% by weight of an αadrenergic receptor agonist selected from the group consisting ofoxymetazoline, naphazoline, tetrahydrozoline, xylometazoline,phenylephrine, methoxamine, mephentermine, metaraminol, midodrine,epinephrine and norepinephrine.

To treat or prevent erythema or a symptom associated therewith, in viewof the present disclosure, the topical aqueous gel composition of theinvention can be topically applied directly to the affected area in anyconventional manner known in the art, e.g., by dropper, applicatorstick, or cotton swab, as a mist via an aerosol applicator, via anintradermal or transdermal patch, or by simply spreading a formulationof the invention onto the affected area with fingers, a sponge, a pad,or wipes. Generally, the amount of a topical formulation of theinvention applied to the affected skin area ranges from about 0.0001g/cm² of skin surface area to about 0.05 g/cm², preferably, 0.002 g/cm²to about 0.005 g/cm² of skin surface area. Typically, one to fourapplications per day are recommended during the term of treatment.

According to a preferred embodiment of the present invention, thetopical aqueous gel composition is topically applied to the affectedskin area once daily.

Methods of the present invention can be used in conjunction with one ormore other treatments and medications for erythema or a symptomassociated therewith, such as the medications used to treat theunderlying disease that causes erythema, antihistamines to controlitching, antibiotics, corticosteroids, intravenous immunoglobulins,acetaminophen, etc.

The other medicament or treatment can be administered to the subjectsimultaneously with, or in a sequence and within a time interval of, theadministration of brimonidine, such that the active ingredients oragents can act together to treat or prevent erythema and symptomsassociated therewith. For example, the other medicament or treatment andbrimonidine can be administered in the same or separate formulations atthe same or different times, i.e., before or after. Any suitable routeof administration can be employed to deliver the additional treatment ormedication.

Another aspect of the invention relates to a packaged product forproviding a safe and effective treatment of erythema or a symptomassociated therewith in a subject. The method comprises:

(1) obtaining a topical aqueous gel composition comprising about 0.01%(w/w) to about 10% (w/w) of an α adrenergic receptor agonist and apharmaceutically acceptable carrier;

(2) devising instructions for topically administering the topicalcomposition to a skin area affected by the erythema or the symptom toobtain the safe and effective treatment; and

(3) providing the topical aqueous gel composition and the instructionsin a unified package.

In one embodiment of the invention, the topical aqueous gel compositionis contained within one suitable container, such as a dropper, a jar, ora tube with a suitable small orifice size, such as an extended tip tube,made of any pharmaceutically suitable material. The topical formulationsaccording to embodiments of the invention can be filled and packagedinto a plastic squeeze bottle or tube. Suitable container-closuresystems for packaging a topical formulations of the invention arecommercially available for example, from Wheaton Plastic Products, 1101Wheaton Avenue, Millville, N.J. 08332. Optionally, an applicator can beprovided in or attached to the container, or separately from thecontainer.

In one embodiment of the invention, the instructions are, for example, apamphlet or package label. The instructions explain how to administertopical aqueous gel formulations of the invention, in an amount and fora period of time sufficient to provide a safe and effective treatment oferythema or a symptom associated therewith. Preferably, the instructionsinclude, for example, the dosage and administration instructions, thetopical aqueous gel formulation's composition, the clinicalpharmacology, drug resistance, pharmacokinetics, absorption,bioavailability, and contraindications.

Another aspect of the present invention relates to a topical aqueous gelcomposition for providing a safe and effective treatment of erythema ora symptom associated therewith in a subject. The topical gel compositioncomprises:

about 0.01% (w/w) to about 10% (w/w) an α adrenergic receptor agonist;and

about 0.20% (w/w) to about 4.0% (w/w) gelling agent.

The topically administrable compositions are prepared by mixing apharmaceutically acceptable carrier with the safe and effective amountof the α adrenergic receptor agonist, such as brimonidine, according toknown methods in the art, for example, methods provided by standardreference texts such as, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY1577-1591, 1672-1673, 866-885 (Alfonso R. Gennaro ed. 19th ed. 1995);Ghosh, T. K.; et al. TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS(1997), both of which are hereby incorporated herein by reference.

In a preferred embodiment, the topical aqueous gel composition comprisesabout 0.4% to about 0.6% by weight of an α adrenergic receptor agonistselected from the group consisting of brimonidine, oxymetazoline,naphazoline, tetrahydrozoline, xylometazoline, phenylephrine,methoxamine, mephentermine, metaraminol, midodrine, epinephrine andnorepinephrine.

More preferably, the topical aqueous gel composition comprises about0.5% by weight of brimonidine tartrate.

Suitable gelling agents known in the art, including those used in thetwo-phase or single-phase gel systems, can be used in the presentinvention. Some examples of suitable gelling agents are disclosed inREMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1517-1518 (Alfonso R.Gennaro ed. 19th ed. 1995), which is hereby incorporated herein byreference. The gelling agents used in embodiments of the presentinvention, include, but are not limited to, one or more hydrophilic andhydroalcoholic gelling agents used in the cosmetic and pharmaceuticalindustries. Preferably, the hydrophilic or hydroalcoholic gelling agentcomprises “CARBOPOL®” (B.F. Goodrich, Cleveland, Ohio), “HYPAN®”(Kingston Technologies, Dayton, N.J.), “NATROSOL®” (Aqualon, Wilmington,Del.), “KLUCEL®” (Aqualon, Wilmington, Del.), or “STABILEZE®” (ISPTechnologies, Wayne, N.J.). The preferred compositional weight percentrange for “CARBOPOL®” is between about 0.5% to about 2%, while thepreferred weight percent range for “NATROLSOL®” and “KLUCEL®” is betweenabout 0.5% to about 4%. The preferred compositional weight percent rangefor both “HYPAN®” and “STABILEZE®” is between 0.5% to about 4%. Otherpreferred gelling agents include hydroxyethylcellulose, cellulose gum,MVE/MA decadiene crosspolymer, PVM/MA copolymer, glycerine polyacrylate,or a combination thereof.

Examples of carbomers that can be used in the present invention include,but are not limited to, Carbomer 910, 934P, 940, 941, 980 and 1342, andCarbopol® 974P and Carbopol® 980. Preferably, the carbomer is Carbomer934P or Carbopol® 974P, and Carbopol® 980.

According to embodiments of the present invention, the amount of thecarbomer in the composition is about 0.5%, 0.6%, 0.7%, 0.8%, 0.85%,0.95%, 1.05%, 1.15%, 1.25%, 1.35%, 1.45%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%or 2.0% (w/w).

In a preferred embodiment, the topical aqueous gel composition comprisesabout 0.4 (w/w) to about 0.6% (w/w) brimonidine tartrate and about 0.8%to 1.5% carbomer.

Polyol gel formulations with various ingredients solubilized thereinhave been used to minimize irritation when applied to the skin of asubject, while ensuring bioavailability of the active agent in theformulation. See Ofher III et al. “Gels and Jellies,” pp. 1327-1344 ofEncyclopedia of Pharmaceutical Technology, vol. 3 (ed. by Swarbrick, etal, pub. by Marcel Dekker, 2002); or Pena, “Gel Dosage Forms: Theory,Formulation, and Processing,” pp. 381-388 of Topical Drug DeliveryFormulations, (ed. by Osborne et al., pub. by Marcel Dekker, Inc.,1990). Polyols in gel formulations can serve one or more functions suchas solubilizing agents, moisturizers, emollients, skin humectant,skin-penetration agents, etc. Suitable polyols that can be used inembodiments of the present invention include, but are not limited to,glycerine, propylene glycol, dipropylene glycol, hexylene glycol,butylene glycol, and liquid polyethylene glycols, such as polyethyleneglycol 200 to 600.

According to embodiments of the present invention, the amount of thetotal polyols in the composition is about 5.0% to 30.0% (w/w), forexample, about 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%,9.5%, 10.0%, 10.5%, 11.0%, 11.5%, 12.0%, 12.5%, 13.0%, 13.5%, 14.0%,14.5%, 15.0%, 17%, 20%, 25% or 30% (w/w).

Preferably, the topical gel composition comprises a first polyol and asecond polyol, such as propylene glycol and glycerine, respectively.

According to embodiments of the present invention, the amount of each ofthe first and second polyols in the composition is independently about 4to 15%, such as 4.5% to 6.5% (w/w), for example, 4.5%, 5.0%, 5.5%, 6.0%or 6.5% (w/w).

The pH of the topical formulations of the invention are preferablywithin a physiologically acceptable pH, e.g., within the range of about4 to about 8, preferably, of about 6 to about 7.5, and more preferablyabout 4.5 to 6.5. To stabilize the pH, preferably, an effective amountof a buffer is included. In one embodiment, the buffering agent ispresent in the aqueous topical formulation in an amount of from about0.05 to about 1 weight percent of the formulation.

The topical gel composition of the present invention can include one ormore other ingredients, such as a protective agent, a cosmetic agent, anadsorbent, a preservative, an antioxidant, a surfactant, askin-penetration agent, local anesthetics, analgesics etc.

In a preferred embodiment, a topical gel composition according toembodiments of the invention further comprises water dispersible form oftitanium dioxide (TiO2), preferably at an amount that is sufficient tomask the color of brimonidine or another colored ingredient in theformulation, but would not cause irritation to the skin. TiO2 may causemild irritation and reddening to the eyes, thus eye contact with theTiO2-containing topically administrable composition should be avoided.Titanium dioxide imparts a whiteness to the topically administrablecomposition and helps to increase the opacity and reduce thetransparency of the composition. Titanium dioxide absorbs, reflects, orscatters light (including ultraviolet radiation in light), which canhelp protect products from deterioration. Titanium dioxide can also beused as a sunscreen to protect the user from the harmful effects ofultraviolet radiation that is part of sunlight.

According to embodiments of the present invention, the amount of waterdispersible form of titanium dioxide in the composition is about 0.04 to0.2%, such as 0.04%, 0.0425%, 0.0525%, 0.0625%, 0.0725%, 0.0825%, 0.09%,0.10%, 0.15%, or 0.20% (w/w).

Suitable preservatives include, but are not limited to, quaternaryammonium compounds, such as benzalkonium chloride, benzethoniumchloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride;alcoholic agents, for example, chlorobutanol, phenylethyl alcohol, andbenzyl alcohol; parabens such as methylparaben, ethylparaben,propylparaben, and butylparaben; antibacterial esters, for example,esters of parahydroxybenzoic acid; and other anti-microbial agents suchas chlorhexidine, chlorocresol, benzoic acid, polymyxin, andphenoxyethanol. Preferably, the preservative is selected from the groupconsisting of sodium benzoate, phenoxyethanol, benzyl alcohol,methylparaben, imidazolidinyl urea and diazolidinyl urea.

In addition to the α adrenergic receptor agonist, such as brimonidine,the topically administrable composition according to embodiments of theinvention can optionally include one or more other pharmaceuticallyactive ingredients, including, but not limited to, one or more other aadrenergic receptor agonist, medications used to treat the underlyingdisease that causes erythema, antihistamines to control itching,antibiotics, corticosteroids, intravenous immunoglobulins,acetaminophen, etc.

This invention will be better understood by reference to thenon-limiting examples that follow, but those skilled in the art willreadily appreciate that the examples are only illustrative of theinvention as described more fully in the claims which follow thereafter.

Example 1 Treatment of Erythema by α-Adrenergic Agonists

This example illustrates the therapeutic effectiveness of variousα-adrenergic agonists in treating erythema.

A number of α-adrenergic agonists were evaluated for their ability totopically suppress erythema in human skin induced by methyl nicotinate.The erythema produced in the skin results from the vasodilatory effecton the dermal vasculature by methyl nicotinate. In this model, theminimum erythemal dose (MED) produced on the forearm by methylnicotinate is determined for each test subject. The MED is defined asthe minimal dose that results in a defined circle of erythema. The MEDwas determined by saturating five 19 mm Hill Top Chambers with 220 μl of1, 2, 3, 4, and 5 mm methyl nicotinate. The Hill Top Chambers wereapplied to the volar forearm of each test subject, removed after 30seconds and excess liquid lightly blotted from the skin. The MED ofmethyl nicotinate was selected 10 minutes after application, bydetermining the minimal dose that resulted in a defined circle oferythema. The α-adrenergic agonists were dissolved in alcohol andtopically applied (2 μl/cm 2) to selected sites on the contralateralvolar forearm for 30 minutes prior to challenge with methyl nicotinate.Hill Top Chambers (19 mm) were saturated with 220 μl of the dose ofmethyl nicotinate determined to produce a MED for each test subject. Thechambers were applied to the volar forearm treated with vehicle or testcompounds, removed after 30 seconds and excess liquid was lightlyblotted from the skin. Ten minutes after application of methylnicotinate the test sites were evaluated for erythema. A numericalgrading scale of 0 to 3 was used: 0=none, 0.5=barely perceptible,1.0=mild, 1.5=mild+(mild to moderate), 2.0=moderate,2.5=moderate+(moderate to severe), 3.0=severe.

The test results are shown in the table below and indicate that each ofthe tested compounds reduced the formation of the Methyl Nicotinateinduced redness (erythema) in the test subjects. With both OxymetazolineHCl and Naphazoline HCl the redness was fully blocked for two of thethree subjects pursuant to the test conditions as described above.

TABLE 1 The Effect of α-Adrenergic Agonists on Methyl Nicotinate-InducedErythema Pre-Treatment + Methyl Nicotinate N Mean Erythema Grade AlcoholVehicle Control 3 3.0 0.2% Naphazoline HCl 3 0.33 0.2% Oxymetazoline HCl3 1.0 0.2% Brimonidine 3 0.83

Example 2

A possible gel formulation of the invention is described in the Table 2below.

TABLE 2 Possible Gel Formulation of the Invention Ingredients Weight %Brimonidine tartrate  1.0% Methylparaben NF 0.15% Propylparaben NF 0.03%Hydroxyethylcellulose 1.25% NF Disodium Edetate 0.05% USP PurifiedWater, USP QS 100%

Example 3

A possible gel formulation of the invention is described in the Table 3below.

TABLE 3 Possible Gel Formulation of the Invention Ingredients Weight %Brimonidine tartrate  1.0% Methylparaben 0.20% Propylparaben 0.05%Carbomer 934P NF  1.0% Sodium Hydroxide QS pH 7 Purified Water USP QS100%

The ingredients are mixed together and aqueous sodium hydroxide isslowly added to the mixture until a pH of about 7 is reached and the gelis formed.

Example 4

A possible gel formulation of the invention is described in the Table 4below.

TABLE 4 Possible Gel Formulation of the invention Ingredients Weight %Brimonidine tartrate 1.0% Methylparaben 0.2% Propylparaben 0.05% “CARBOPOL ®” 1.0% Triethanolamine QS pH 7 Water QS 100%

The ingredients are mixed together and stirred. Triethanolamine is addeduntil a pH of about 7 is attained.

Example 5

This example illustrates additional topical aqueous gel formulationsthat can be used in the present invention.

A first group of additional gel formulations is described in Table 5below.

TABLE 5 Ingredients % (w/w) % (w/w) % (w/w) α-adrenergic agonist0.3-0.6% 0.6-3% 3-10% Methylparaben NF 0.15% 0.20% 0.10% PropylparabenNF 0.03% 0.02% 0.04% Hydroxyethylcellulose NF  1.0% 1.25%  1.5% Butyleneglycol 1,3  3.0%  6.0% 18.0% Glycerine  2.0%  4.0% 12.0% DisodiumEdetate USP 0.05% 0.05% 0.05% Purified Water, USP QS QS QS TOTAL  100% 100%  100%

The pH of the formulation is adjusted to about 4.5 to 7.0.

A second group of additional gel formulations is described in Table 6below.

TABLE 6 Ingredients % (w/w) % (w/w) % (w/w) α-adrenergic agonist0.3-0.6% 0.6-3.0% 3.0-10% Methylparaben 0.20% 0.20% 0.20% Propylparaben0.05% 0.05% 0.05% KLUCEL ®  2.0%  2.5%  1.0% Propylene glycol   3%   6%  15% Glycerine, USP   3%   6%   15% 10% Titanium dioxide  0.5%  0.6% 0.7% Purified Water, USP QS QS QS TOTAL  100%  100%  100%

The ingredients are mixed together and aqueous sodium hydroxide isslowly added to the mixture until a pH of about 4.5 to 6.5 is reachedand the gel is formed.

A third group of additional gel formulations is described in Table 7below.

TABLE 7 Ingredient % (w/w) % (w/w) % (w/w) α-adrenergic agonist 0.3-0.6%0.6-3.0% 3.0-10% Carbomer 934P 1.25%   1.0% 1.5% Methylparaben 0.2%0.15% 0.20%  Phenoxyethanol 0.4% 0.35% 0.4% Glycerol 5.5%   10%  15%Kowet titanium dioxide 0.0625%   0.0725%   0.0825%   Propylene glycol5.5%   10%  15% DI Water QS QS QS TOTAL 100%  100%  100% 

The ingredients are mixed together and aqueous sodium hydroxide isslowly added to the mixture until a pH of about 4.5 to 6.5 is reachedand the gel is formed.

A fourth group of additional gel formulations is described in Table 8below.

TABLE 8 Ingredients % (w/w) % (w/w) % (w/w) α-adrenergic agonist0.3-0.6% 0.6-3.0% 3.0-10% Methylparaben 0.15%  0.125% 0.1% Propylparaben0.05%   0.05% 0.06%  Carbopol ® 980 1.0%  0.8% 1.5% Glycerin 5.5%   10% 15% 10% Titanium dioxide 0.575%  0.675% 0.775%  Polyethylene glycol4.5%    8%  12% Water QS QS QS TOTAL 100%    100% 100% 

The ingredients are mixed together and stirred. Triethanolamine is addeduntil a pH of about 5.5 to 7.0 is attained.

Example 6 Comparative Bioavailability and Pharmacokinetics Study ofBrimonidine Compositions

This study was a randomized, evaluator-blinded, intra-individualcomparative pharmacokinetic study of brimonidine tartrate, ophthalmicsolution (0.2%) and topical gel (0.07%, 0.18% and 0.50%) applied undermaximal use conditions for 29 days in subjects with moderate to severeerythema associated with rosacea. Major entrance criteria includedclinical diagnosis of moderate to severe facial erythema associated withrosacea, CEA score ≧3, and IOP level 11-21 mmHg. Intra-subjectcomparison of topical to ophthalmic exposure following one day treatmentwith brimonidine tartrate ophthalmic solution 0.2% was performed.

A total of 102 subjects were randomized: 24, 26, 25, and 27 subjects in0.5% Gel QD, 0.18% Gel BID, 0.18% Gel QD, and 0.07% Gel BID,respectively. On the Day 1 visit, one drop of brimonidine tartrateophthalmic solution 0.2% was administered to each eye every 8 hours overa 24 hour period. After a 2-day wash-out period, one gram of topical gel(0.07%, 0.18%, or 0.50% of brimonidine tartrate) was applied once (QD)or twice daily (BID) to the face of subjects for 4 weeks.

Blood samples for complete PK profiling were taken during the 24-hourocular treatment (study Day 1) and during the first day of topicalapplication (study Day 4), fifteen days of topical application (studyDay 18) and after the last topical application up to 72 hours post-dose(study Day 32). Additional blood samples were collected beforeapplication (Day 10, Day 24). Brimonidine plasma concentrations weredetermined by using a validated LC-MS/MS method with a lower limit ofquantification (LOQ) of 10 pg/mL.

The PK parameters for brimonidine were calculated using standardnon-compartmental method and C_(max), AUC_(0-24hr) were analyzedstatistically using log-transformed data. For both the differencesbetween times administration routes and between treatment groups, thelimits of the intervals were back-transformed into exponential to obtain90% confidence intervals (90% CI) of the ratios of geometric means onthe original scale. The statistical analysis was performed using allC_(max) (BLQ values being replaced by the LOQ) and using onlyquantifiable AUC_(0-24hr).

PK results demonstrated that:

(1) Ocular treatment: Administration of brimonidine tartrate 0.2% byophthalmic route resulted in quantifiable exposure (>10 pg/mL) in allpatients receiving TID treatment. The pharmacokinetic (PK) parameters ofthe ophthalmic solution have a mean C_(max) of 54±28 pg/mL (range:16-134 pg/mL) and a mean AUC_(0-24hr) of 568±277 pg·hr/mL (range:124-1490 pg·hr/mL). These were consistent with the known data ofbrimonidine tartrate 0.2% (w/w) ophthalmic solution, e.g., NDA:21-262,0.2% Brimonidine Purite Multiple dose TID, C_(max) 65±38 pg/mL.

(2) Topical treatments: Daily topical application of brimonidine Gel for29 days resulted in quantifiable (>10 pg/mL) systemic exposure in 24%,48%, 68% and 75% of subjects receiving brimonidine Gel 0.07% BID, 0.18%QD, 0.18% BID or 0.5% QD, respectively. At the end of the treatmentperiod, the mean (±SD) C_(max) were 13±9 pg/mL 17±20 pg/mL, 17±10 pg/mL,25±24 pg/mL for brimonidine Gel 0.07% BID, 0.18% QD, 0.18% BID or 0.5%QD, respectively. Quantifiable AUC_(0-24hr) were 172±87 pg·hr/mL,183±113 pg·hr/mL, 267±119 pg·hr/mL, 364±216 pg·hr/mL for brimonidine Gel0.07% BID, 0.18% QD, 0.18% BID or 0.5% QD, respectively.

The effect of multiple dose of brimonidine gel on PK profile (Timeeffect: Day 4/Day 18/Day 32) was assessed for each topical treatmentgroups. Systemic exposures of the first day of topical application werecomparable to those observed after 29 days topical applications in alltreatment groups, thus suggesting that there is no drug accumulationthroughout the treatment duration (i.e. 4 weeks) whatever the dose andthe dose regimen. Whatever the dose and dose regimen tested, theOcular/Topical ratios calculated over the entire topical treatmentperiod (Day 4, Day 18 and Day 32) was significantly lower than 1.

After topical application of brimonidine gel, systemic exposureincreases with applied dose. However, statistical analysis showed thatsystemic exposure (C_(max)) is not dose proportional. The mean C_(max)increased lower than dose proportionality.

The topical systemic exposure (expressed as C_(max) or AUC_(0-24hr))from the skin treatment was compared to the one obtained after oculartreatment. See Table 9.

TABLE 9 statistical comparison of the ocular and topical treatmentsCD07805/47 Gel CD07805/47 Gel CD07805/47 Gel CD07805/47 Gel 0.5% QD0.18% BID 0.18% QD 0.07% BID Parameter Estimate (90% CI) Estimate (90%CI) Estimate (90% CI) Estimate (90% CI) Cmax Ratio between TopicalAdministration Visit and Day 1 (Ophthalmic administration) Day 4/Day 10.3 (0.3, 0.3) 0.3 (0.2, 0.3) 0.2 (0.2, 0.3) 0.2 (0.2, 0.2) Day 18/Day 10.6 (0.5, 0.7) 0.3 (0.3, 0.4) 0.2 (0.2, 0.3) 0.2 (0.2, 0.2) Day 32/Day 10.4 (0.3, 0.4) 0.3 (0.3, 0.4) 0.3 (0.2, 0.3) 0.2 (0.2, 0.3) QuantifiableAUC_(0-24 hr) Ratio between Topical Administration Visit and Day 1(Ophthalmic administration) Day 4/Day 1 0.6 (0.4, 0.7) 0.4 (0.3, 0.5)0.3 (0.2, 0.4) 0.1 (0.1, 0.3)^(a) Day 18/Day 1 0.7 (0.6, 0.9) 0.5 (0.4,0.6) 0.3 (0.2, 0.4) 0.5 (0.2, 0.8)^(a) Day 32/Day 1 0.5 (0.4, 0.7) 0.5(0.4, 0.6) 0.3 (0.2, 0.4) 0.4 (0.3, 0.7)^(a) ^(a)should be taken withcare due to the limited number of quantifiable AUC_(0-24hr) (2 to 6)N.B.: Day4 → first topical administration; Day 18 → 15th topicaladministration; Day 32 → 29th and last topical administration

In all the dosages and dose regimens tested the Ocular/Topical ratioscalculated over the entire duration of the topical treatment period (Day4, Day 18 and Day 32) were significantly lower than 1. The C_(max) meanratio was 0.2 for 0.07% BID group, ranged from 0.2 to 0.3 for 0.18% QDand BID groups and ranged from 0.3 to 0.6 for 0.5% QD group. ForC_(max), the upper limit of the 90% confidence interval did not include0.8 whatever the dose and dose regimen tested. The highest ratio wasobserved in the 0.5% QD group (mean ratio 0.6, 90% CI [0.5-0.7]) after15 days of application, but not confirmed at the end of the 29-day oftopical treatment (mean ratio 0.4, 90% CI [0.3-0.4]). The same tendencywas observed with the quantifiable AUC_(0-24hr). The clinical resultsdemonstrated that the systemic exposure obtained after topical treatmentwith all concentrations and regimens tested in the study issignificantly lower compared to the systemic exposure obtained with theeye drops applied as recommended in the label of the ophthalmicproducts.

In conclusion, quantifiable PK profiles (at least C_(max)) were observedin all treatment groups. It has been found that although systemicexposure increased with the applied dose of brimonidine, statisticalanalysis showed that the increase in systemic exposure (C_(max)) was notdose proportional, i.e., the increase in the mean C_(max) was much lessthan the increase in the dose. No evidence for systemic accumulation wasobserved.

All evaluated concentrations and regimens were well tolerate and safe.No clinically meaningful reductions in mean IOP, vital signs or routinelaboratory parameters were observed with any of the topical geltreatment groups. Increasing drug concentration or regimen had no effecton the incidence of related cardiac/vascular AEs. There is noidentifiable relationship between any PK parameter and the incidence orseverity of any AEs related to the topical gel. There were no SAEsreported during the treatment period with the topical gel for skinapplication (DAY 4 through study completion). Two SAEs were reportedduring the ophthalmic solution treatment period (DAYS 1-3) in twosubjects, with one SAE (Acute Hypotensive Event) considered related tothe ophthalmic solution. Both subjects with SAEs were discontinued fromthe study prior to any exposure to the topical gel.

The study results demonstrated that the systemic exposure obtained aftertopical treatment of the affected skin areas with all concentrations ofbrimonidine and regimens tested is significantly lower compared to thesystemic exposure obtained with the eye drops (0.2% by weightbrimonidine tartrate) applied as recommended in the label of theophthalmic products.

Based on results from this comparative bioavailability andpharmacokinetics study, concentrations of brimonidine higher than 0.2%(w/w) can be used for topical administration to an affected skin areafor safe and effective treatment of a skin disorder.

Example 7 Clinical Study on the Effectiveness and Safety of BrimonidineTartrate Gel Compositions

This was a 4-week treatment with 4-week follow-up, randomized,double-blind, parallel-group, vehicle-controlled, multicenter studyinvestigating the efficacy and safety of a topical gel compositioncontaining 0.5% brimonidine tartrate (Gel 0.5%) applied topically oncedaily (QD) and a topical gel composition containing 0.18% brimonidinetartrate (Gel 0.18%) applied topically once daily (QD) or twice daily(BID) compared to Vehicle Gel applied topically once daily (QD) or twicedaily (BID), to affected skin areas of subjects with moderate to severefacial erythema associated with rosacea.

Major entrance criteria included clinical diagnosis of moderate tosevere facial erythema associated with Rosacea, CEA score ≧3 and PSA-5score ≧3, presence of no more than 2 facial lesions, and IOP level atleast 10 mmHg.

Qualified subjects were randomized in a 1:1:1:1:1 ratio (block size of5) to one of the five treatment arms (0.5% QD, 0.18% BID, 0.18% QD,Vehicle BID, Vehicle QD).

A total of 269 subjects from 17 clinical sites were randomized toTopical Gel or Vehicle Gel: 53, 54, 54, 53, and 55 subjects in the 0.5%QD, 0.18% BID, 0.18% QD, Vehicle BID, and Vehicle QD arms, respectively.All 269 subjects were included in the ITT and Safety population, and 237subjects were included in the PP population.

CEA and PSA evaluation data were collected at each clinic visit at Hours3, 6, 9, and 12 after study drug application. Data collected at 30minutes after study drug application comprised the secondary endpointsof CEA Initial Effect and PSA Initial Effect. Subject-reported efficacydata were collected at clinic visits and on non-clinic days during thetreatment period. Safety were assessed throughout the study.

The primary endpoint, Composite Success, is defined as a 2-gradeimprovement on both CEA and PSA-5 measured at Hours 3, 6, 9 and 12 onDay 29 after the treatment. Statistical analysis was performed tocompare each active treatment (0.5% QD, 0.18% BID and QD) vs. thecorresponding Vehicle QD or Vehicle BID, respectively. Additionalanalyses for Composite Success on early treatment visits Day 15 and Day1 were performed to further investigate the early treatment effect.

Maximal drug effect peaked between approximately 3 to 6 hours afterdosing. On Day 29, statistically significant difference between 0.5% QDvs. Vehicle QD was observed (p<0.001). Consistently, the samesuperiority of 0.5% QD vs. Vehicle QD was observed on Day 15 (p<0.001)and Day 1 (p<0.001). The statistical results based on the ITT population(LOCF approach) were confirmed in the population point (PP) populationand three sensitivity analyses (i.e. imputing missing data by assigningfailure, success, and average data, respectively).

As shown in FIG. 1, superior treatment effect was clearly demonstratedin 0.5% QD, followed by 0.18% BID and QD. Consistently, 0.5% QD showedstrong and robust effect as measured by Composite Success throughout the12 hour duration, starting on Day 1 and continued till Day 29.Therefore, no evidence of tachyphylaxis was observed. The magnitude ofthe treatment effects were general similar between 0.18% BID and 0.18%QD. The lower vehicle effect in the Vehicle QD regimen resulted inbetter statistical outcome for 0.18% QD vs. Vehicle QD comparison.

In addition to the analysis on Composite Success, which is definedjointly by two independent static assessments, CEA-Success and PSA-5Success were also analyzed individually. The magnitudes of theCEA-Success (FIG. 2) and PSA-5 (FIG. 3) Success were greater in alltreatment groups compared to Composite Success but the pattern of therelative effects was same as observed in Composite Success.Consistently, 0.5% QD showed the greatest effect for CEA Success andPSA-5 Success; 0.18% QD and BID showed numerically better effectcompared to Vehicle QD and BID, respectively.

The conclusion based on Composite Success, CEA-Success and PSA-5 Successwas supported by PSA-5 Diary data (i.e. the subjects' daily recording oftheir facial redness) during the study.

The overall incidence of related adverse events (AEs) for the study waslow. The number of related AEs was comparable between the treatmentgroups, and there was no significant difference in incidence of relatedadverse events between active and vehicle treatment arms. There was nosignificant increase in the number or severity of systemic or topicalrelated AEs with increase in gel concentration or application frequency.No severe related AEs were reported during the study. There were noreported systemic cardiac AEs considered related to the studymedication. No case of related facial flushing led to studydiscontinuation or interruption of daily treatment.

No clinically meaningful abnormal trends or shifts were observed in meanblood pressure (systolic and diastolic) or heart rate for any of thetreatment groups during the treatment phase (Days 1, 15, and 29) or atthe end of the follow-up period, and there was no observable differencein mean blood pressure or heart rate changes between active and vehiclearms. Increasing drug concentration or application frequency had noeffect on the incidence of isolated vital sign abnormalities. There wereno reported adverse events of acute hypotension, bradycardia, or syncopeduring the study.

This clinical study demonstrated that Gel 0.5% QD possessed superiorefficacy compared to the corresponding vehicle and Gel 0.18% QD and BIDtreatments evaluated in the study (primary endpoint: Composite Successdefined as a 2-grade improvement on both CEA and PSA-5 at Hours 3, 6, 9,and 12 on Day 29). The primary outcome was supported by the secondaryendpoints. No unacceptable drug related adverse event was observed.Safety and tolerability of Gel 0.5% QD is favorable. No evidence oftachyphylaxis or rebound was found in the study.

Unlike ophthalmic applications of brimonidine, where the chronic use oflower concentration of brimonidine, e.g., 0.1% (w/w), provides improvedtolerability while maintaining IOP-lowering efficacy, the presentclinical studies unexpectedly discovered that higher concentrations ofbrimonidine provide significantly improved clinical efficacy in treatingerythema or related symptoms, while not causing any observable change inpatient safety and tolerability as compared to lower concentrations ofbrimonidine.

It will be appreciated by those skilled in the art that changes could bemade to the embodiments described above without departing from the broadinventive concept thereof. It is understood, therefore, that thisinvention is not limited to the particular embodiments disclosed, but itis intended to cover modifications within the spirit and scope of thepresent invention as defined by the appended claims.

I/We claim:
 1. A method of treating erythema or a symptom associated therewith in a subject, the method comprising topically administering to a skin area of the subject a topical composition comprising about 0.01% to about 10% by weight of at least one alpha 2-adrenergic receptor agonist and a pharmaceutically acceptable carrier, wherein the skin area is, or is prone to be, affected by the erythema or the symptom associated therewith.
 2. The method of claim 1, wherein the topical composition is selected from the group consisting of an aqueous solution topical formulation, cream topical formulation, and ointment formulation.
 3. The method of claim 1, wherein the erythema is erythema of rosacea.
 4. The method of claim 1, wherein the at least one alpha 2-adrenergic receptor agonist is a non-selective alpha 2-adrenergic receptor agonist.
 5. The method of claim 1, wherein the at least one alpha 2-adrenergic receptor agonist is brimonidine or a pharmaceutically acceptable salt thereof.
 6. The method of claim 5, wherein the at least one alpha 2-adrenergic receptor agonist is brimonidine tartarate.
 7. The method of claim 1, further comprising administering to the subject at least one additional treatment and medication for erythema or the symptom associated therewith.
 8. The method of claim 1, wherein the topical composition is a topical aqueous gel composition.
 9. The method of claim 1, wherein the topical composition is administered to the skin area once daily.
 10. The method of claim 1, wherein the topical composition comprises about 0.6%-3% by weight of the at least one alpha 2-adrenergic receptor agonist.
 11. The method of claim 1, wherein the topical composition comprises about 0.05%-1% by weight of the at least one alpha 2-adrenergic receptor agonist.
 12. The method of claim 1, wherein the topical composition comprises about 0.3%-0.6% by weight of the at least one alpha 2-adrenergic receptor agonist.
 13. The method of claim 1, wherein the topical composition comprises about 0.4%-0.6% by weight of the at least one alpha 2-adrenergic receptor agonist.
 14. The method of claim 1, wherein the topical composition comprises about 0.5% by weight of the at least one alpha 2-adrenergic receptor agonist.
 15. The method of claim 1, wherein the topical administration of the topical composition to the skin area results in significantly more reduction of the erythema and the symptom compared to a vehicle control as measured by a 12 hour success profile evaluated on both CEA and PSA scales, without causing any unacceptable adverse effect, wherein the 12 hour success profile comprises a noticeable effect of 1-grade improvement of the erythema or the symptom and about 1 hour to about 8 hours of 2-grade improvement of the erythema or the symptom.
 16. A method of treating erythema or a symptom associated therewith in a subject, the method comprising topically administering to a skin area of the subject a topical aqueous gel composition comprising about 0.01% to about 10% by weight brimonidine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the skin area is, or is prone to be, affected by the erythema or the symptom associated therewith.
 17. The method of claim 16, wherein the erythema is facial erythema associated with rosacea, and the topical administration of the topical aqueous gel composition to the skin area results in significantly more reduction of the facial erythema compared to a vehicle control as measured by a 12 hour success profile evaluated on both CEA and PSA scales, without causing any unacceptable adverse effect, wherein the 12 hour success profile comprises a noticeable effect of 1-grade improvement of the facial erythema and about 3 hours to about 6 hours of 2-grade improvement of the facial erythema.
 18. A method of treating erythema or a symptom associated therewith in a subject, the method comprising topically administering to a skin area of the subject a topical composition comprising about 0.4 (w/w) to about 0.6% (w/w) brimonidine tartrate and about 0.8% (w/w) to about 1.5% (w/w) carbomer and a pharmaceutically acceptable carrier, wherein the skin area is, or is prone to be, affected by the erythema or the symptom associated therewith.
 19. The method of claim 18, wherein the topical composition is a topical aqueous gel composition.
 20. The method of claim 19, wherein the erythema is facial erythema associated with rosacea, and the topical administration of the topical aqueous gel composition to the skin area results in significantly more reduction of the facial erythema compared to a vehicle control as measured by a 12 hour success profile evaluated on both CEA and PSA scales, without causing any unacceptable adverse effect, wherein the 12 hour success profile comprises a noticeable effect of 1-grade improvement of the facial erythema and about 3 hours to about 6 hours of 2-grade improvement of the facial erythema. 